We propose to produce and measure subtle degrees of damage to the hematopoietic system with small doses of known hematopoietic toxins, and then carry this approach over to the study of small doses of irradiation or environmental pollutants, in the dose range not generally considered to be harmful to the blood-forming system. This necessitates use of an in vivo mouse model in which the hematopoietic reserve has been removed by administration of 89Sr followed by splenectomy. Once we have established and recorded the impairment of one or more components of hematopoiesis, we will investigate the degree to which repeated exposures, or combinations of several different agents, may be cumulative. In addition to studying damage to the primitive precursor cell compartments, we will be searching for and attempting to establish methods for assessing damage to the stroma or hematopoietic microenvironment. Finally, a long-term objective is to determine whether one or a series of very small insults to the bone marrow and its microenvironment by various pollutants or hematopoietic toxins may contribute to leukemogenesis.